New Trends in the Diagnosis and Therapy of Alzheimer’s Disease

149 Pages·1994·3.5 MB·English

by  R. D. Terry M.D.

KEY TOPICS
IN BRAIN
RESEARCH
Edited b A. Carl son, P. Riederer,
H. Beckmann, T. Nagatsu,
S. Ger hon, and K. A. Jellinger
K. A. fellinger, G. Ladurner,
and M. Windisch (eds.)
ew Trends in the
Diagnosis and Therapy
of Alzheimer's Disease
Springer-Verlag Wien New York
Prof. Dr. K. A. Jellinger
Ludwig Boltzmann Institute of Clinical Neurobiology,
Lainz Hospital, Vienna, Austria
Prof. Dr. G. Ladurner
Department of Neurology, Landesnervenklinik,
Salzburg, Austria
Dr. M. Windisch
Department of Research and Development,
Ebewe Pharmaceuticals Ltd., Unterach, Austria
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© 1994 Springer-Ver!ag/Wien
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With 33 Figures
ISSN 0934-1420
ISBN-13 :978-3-211-82620-1 e-ISBN-13 :978-3-7091-9376-1
DOl: 10.1007/978-3-7091-9376-1
Preface
Alzheimer's disease, the most common form of adult-onset demen
tia, is a major health and socio-economic problem which will continue
to intensify with the increasing life expectancy and the continuing
increase of the elderly in the population. Alzheimer dementia is one of
the most frequent diseases in the eldery comparable in incidence to the
risk of myocardial and/or cerebral infarction. It has become one of the
leading causes of death in modern society. According to recent US
studies the economic and social costs of Alzheimer disease patients
who need substantial caregiving either by their family or public insti
tutions were US $ 47.581 and 173.932 per case, respectively. The
estimated 1991 national direct and total prevalence costs were $ 20.6
and 67.3 billion, respectively. Assuming that the prevalence of the
disease remains constant, the estimated discounted present values of
the direct and total costs of all current and future generations of
Alzheimer's patients are $ 536 billion and $ 1.75 trillions, respectively
[Ernst and Hay (1994) Am J Public Health 84: 12611. Despite consider
able progress in molecular genetic research, the causes of Alzheimer's
disease are still unknown. Although the accuracy of making the clinical
diagnosis of Alzheimer dementia, at least in advanced stages of the
disease, is over 90%, difficulties remain in the early diagnosis and its
differentation from effects of normal aging, depression and other
treatable dementias. Homogeneity in clinical diagnosis and the staging
of dementia using standardized criteria and modern neuroimaging
methods are the basis of successful treatment strategies, the effectivity
of which, up to the present, is rather limited. This volume in the series
"Key Topics in Brain Research" presents the updated papers read at the
2nd International Symposium of Research Initiative EBEWE on "New
Trends in the Diagnosis and Therapy of Alzheimer's Disease" held in
October 1993 at Salzburg. They give an overview of our current
knowledge on morphology, neuroimaging, neurochemical markers,
psychopathology and drug treatment of Alzheimer disease and related
dementing disorders in the elderly. Although the current possibilities
of anti-dementia drug therapy are limited, and there is still lack of
adequate standard treatment strategies, the use of nootropic substances
targeted to specific symptoms has been proven in controlled clinical
VI Preface
trials. Considerable improvement of neuropsychological performance,
every-day activity, and cerebral metabolism has heen established. The
therapeutic efficacy of these and other substances, however, must he
proven in further controlled clinical trials. This volume is aimed to
provide information about the current trend and limits of diagnosis and
therapy of Alzheimer's disease. The Symposium and the edition of this
book would not have been possible without the generous support of
Ebewe Pharmaceuticals, Ltd. The secretarial help of Mr. K. Paukner,
1. Boltzmann Institute of Clinical Neurobiology, Vienna, is acknowl
edged. Finally, we are grateful to Springer-Verlag Wien for the perfect
cooperation and the excellent production of this book.
October 1994 K. JEI.U:\GER
G. LADllR0:ER
E. WI:\])]SCII
Contents
Teny, R. D., Masliah, E.: Synaptic pathology in the pathogenesis of
Alzheimer dementia .......................... ........ 1
fellinger, K A., Eancher, c.: Classification of dementias based on func-
tional morphology ............................... 9
Aichner, F. T, Felber, S. R., Birbamer, G. G.: Computed tomography and
magnetic resonance imaging in the diagnosis of Alzheimer's disease 41
Heiss, W.-D.: Diagnostic imaging techniques with special reference to
PET .......................................... 53
Frolich, L., Dirr, A., Gotz, M. E., Taneli, Y, Thome,]., Lesch, K P., Ihl, R.,
Dierks, T, Blum-Degen, D., Riederer, P., Maurer, K: Neurochemical
investigations in patients with dementia of Alzheimer type and their
clinical value .................................. 69
Stemmler, M., Stein wachs, K-C., Lehfeld, H.,Jentzsch,J., Tritt, K, Hulla,
F. W., Erzigkeit, H.: Different methodological approaches for the
construction of a therapy sensitive ADL scale for the assessment of
Alzheimer patients . . . . . . . . . . . . . . . . . . . . . . 81
Panisset, M., Gauthier, S.: Trial designs and outcome variables in anti-
dementia drug testing .. ............. 91
Oswald, W. D., Tritt, K: Cognitive deterioration in old age and in the
course of dementia ......... . . . . . . . . . . . . . . . . . . 105
Knusel, B., H~fti, F.: NGF and Alzheimer's disease: a model for trophic
factor therapy in neurodegeneration ....................... 115
Ruether, E., Ritter, R., Apecechea, M., Freitag, S., Windisch, M.: Efficacy of
Cerebrolysin® in Alzheimer's disease . . . . . . . . . . . . . . . . . .. 131
Subject Index .................................... . 143
Synaptic pathology in the pathogenesis of
Alzheimer dementia
R.D. Terry and E. Masliah
Department of Neurosciences, University of California San Diego,
Ll Jolla. Ca. U.S.A.
Summary
Whereas the number of cortical neurons in human brain does not signifi
cantly change with age, there is a significant reduction of synaptic terminals in
both normal aging brain and Alzheimer's disease (AD). Multivariant analysis of
a cohort of AD patients showed a highly significant correlation between
psychostatus and reduction of midfrontal synapses and large neurons, while
there was no correlation with amyloid deposits. Another \'ariable contributing
to cognitive decline are numbers or neurofibrillalY tangles and neuron loss in
the cholinergic nucleus basalis of Meynert These and other recent morphologic
data do not support the hypothesis that amyloid deposition is a major patho
genic factor of both neuronal and synaptic loss in aging and AD. The causes of
synaptic pathology in AD remain to be elucidated.
Introduction
Normal, disease-free aging involves a wide variety of physiologic
and structural changes in several organ systems. For example, the lungs
lose elasticity and skeletal muscles undergo atrophy. Such changes in
the brain are also significant, involving loss and/or shrinkage of neu
rons in the neocortex and elsewhere, but not evelywhere. But perhaps
of greater cognitive significance is the loss of neocortical synapses. In
regard to neuronal populations, Brody reported in 1955 that in normal
aging there is a major loss of cortical neurons, especially the smaller
ones. However, he studied relatively few cases, and these were not
repo11ed as to their clinical hist01Y, nor were they examined for the
presence of plaques or tangles. Subsequently, Terry et aL (1987)
reported that three cortical association areas in 51 brain from clinically
2 ltD. Tt'ITV and L '\lasliah
normal and histologically intact incli\iduals displayed a loss of large
neurons, but an equi\'alent increase of small neurons. so that the
total normal number of neuronal somata did not significantly change
over a neurologically normal age range from 24 to 100 years. The
data indicated that large neurons atrophied to join the small neuron
classes.
During the past fe\\' years several reports have appeared concerning
synapse populations. Scheff et al. (993) used electron microscopy,
identif\'ing the synapse by its pre-and post-gap terminals with the
characteristic post synaptic density. Our laboratolY group has devel
oped several immunochemical (Alford et aI., 1993) and immuno
cytochemical methods (Ivlasliah et aI., 1990) \vhich allow a larger area
to be measured with greater efficiency. These later techniques depend
on an immunoreaction with an antibody against synaptophysin, a
protein of 38 kd which is integral to the memhrane of the synaptic
vesicle. The label thus localizes the presynaptic bouton. lItilizing
confocal laser scanning microscopy of sections double laheled \vith
anti-amyloid and anti-synaptophysin, we examined dorsal frontal cor
tex of 25 individuals (not the same people as those ahove) without
dementia ranging from 16 to 98 years of age (Masliah et a1.. 1<)<)1('), An
approximately linear decrease in the number of synapses per unit area
\\'as noted, and it had a correlation coefficient ® with age of -0.708.
significant at 0.0001. There was a 201X) difference hetween the group
(wer 60 years old and those younger than 60. We propose that the loss
of cortical synaptic terminals is related to shrinkage and/ur loss of the
projection neurons, in that a shrunken projection neuron can be
presumed to be less able to maintain its normally large synaptic arbor
at the distant terminal of its axon. On the other hand, local events such
as altered extracellular matrix or cell membrane oat or near the synaptic
terminal can not be ruled out as a cause of the synaptic loss in either
normal aging or in Alzheimer disease.
As to Alzheimer disease, it must he kept in mind that the disorder
is superimposed on \\hate\'er aging changes ha\'e taken place and are
continuing at the time of the disease onset and throughout the
course. This implies that there need be less structural or chemical
difference between the normal hrain and a diseased one both at
advanced age than there is if the disease occurs at a younger age.
Indeed. this is the case in regard to all the histologic changes. Younger
victims have far more plaques, tangles, neuronal and synaptic loss than
do the older ones at the same stage of dementia (Hansen et aI., 1988).
This would seem to be because the older ones are closer to that
threshold of synaptic reserve helow \vhich clementia \vill he come
apparent. This concept also implies that if a person starts adult life \\'ith
a smaller numher of synapses because of genetic or, perhaps. educl
tional or other environmental effects, the onset of the disease \vill he
earlier.
Synaptic pathology in the pathogenesis of Alzheimer dementia 3
Material and methods
As noted above, Scheff et al. (993) have reported a highly significant loss
of neocOitical synapses in Alzheimer disease by the use of electron microscopy
of both biopsy and autopsy tissue. We, on the other hand, have utilized three
techniques on autopsy tissue: microdensitometty of peroxidase reacted anti
synaptophysin (Masliah et aI., 1990), confocal quantification of fluorescent
markers (Masliah et a1., 1991a), and a quantitative dot-blot (Alford et a1., 1993).
All have shown a \'ery se\'ere loss (40-50%) of presynaptic terminals relative to
age-matched controls. There was little or no overlap between the normals and
the AD patients. When, rarely, a synapse measure was in the range of normal
in an AD patient's frontal cortex, the same brain displayed a count below the
normal range in the parietal lobe.
Our Alzheimer patients had undergone extensive psychometric studies
during their periodic workups in the Alzheimer Disease Research Center.
Included among the administered tests ,vere the Blessed [nformation Memory
Concentration test (TMC) (Blessed et aI., 1968) as modified for American
use (Fuld, 1978), the Mini-Mental State Examination (MMSE) of Folstein et a1.
(1975) and the Dementia Rating Scale (DRS) of Mattis (976). The first is largely
a test of memory, while the second emphasizes other cognitive abilities. The
DRS has competent items \\'hich can still be answered in the later stages of
the disease so that it does not reach a floor as early in the course as the
other two.
Results and comments
In our series (Terry et al., 1991) as measured by the micro
densitometlY method, the IMC correlated with a frontal synapse score
at r = 0.729. The correlation of the DRS with MF synapse measurement
was r = 0.673. Step-wise regression analysis was applied in order to
evaluate the relative strength of neuron counts, plaques, tangle,
synapse measures and concentrations of choline acetyltransferase, all
from the same three cortical areas - midfrontal eMF), superior temporal
CST), and inferior parietal (IP), These multivariate analyses also in
cluded the patients' midfrontal synapses provided ,76 of the final r,
inferior parietal plaques added another ,15, and midfrontal plaques
added ,03 to the final coefficient of .94, yielding a variance of 88%, As
to the MMSE the midfrontal synapses provided ,73, inferior parietal
plaques added, 12, inferior parietal synapses another .04 and midfrontal
choline acetyltransferase added 0,04 for a total coefficient of ,93 and a
variance of 86%, With the DRS, midfrontal synapses contributed ,67,
inferior parietal plaques added .25, and inferior parietal synapses ,04
for a total coefficient of .96 and variance of 92% (Table 1). Those
parameters not mentioned in regard to multivariant analyses did not
figure significantly in the calculation. Note especially that plaques
contributed only a quarter or less of the strength of these correlations,
It \vas also interesting that the rostral superior temporal region (area 38)